Design of potent inhibitors of human RAD51 recombinase based on BRC motifs of BRCA2 protein: modeling and experimental validation of a chimera peptide.
Stasiak, Alicja Z
KAUST Grant NumberKUK-11-008-23
Online Publication Date2010-07-19
Print Publication Date2010-08-12
Permanent link to this recordhttp://hdl.handle.net/10754/596780
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AbstractWe have previously shown that a 28-amino acid peptide derived from the BRC4 motif of BRCA2 tumor suppressor inhibits selectively human RAD51 recombinase (HsRad51). With the aim of designing better inhibitors for cancer treatment, we combined an in silico docking approach with in vitro biochemical testing to construct a highly efficient chimera peptide from eight existing human BRC motifs. We built a molecular model of all BRC motifs complexed with HsRad51 based on the crystal structure of the BRC4 motif-HsRad51 complex, computed the interaction energy of each residue in each BRC motif, and selected the best amino acid residue at each binding position. This analysis enabled us to propose four amino acid substitutions in the BRC4 motif. Three of these increased the inhibitory effect in vitro, and this effect was found to be additive. We thus obtained a peptide that is about 10 times more efficient in inhibiting HsRad51-ssDNA complex formation than the original peptide.
CitationNomme J, Renodon-Cornière A, Asanomi Y, Sakaguchi K, Stasiak AZ, et al. (2010) Design of Potent Inhibitors of Human RAD51 Recombinase Based on BRC Motifs of BRCA2 Protein: Modeling and Experimental Validation of a Chimera Peptide. Journal of Medicinal Chemistry 53: 5782–5791. Available: http://dx.doi.org/10.1021/jm1002974.
SponsorsWe thank Drs. Fabrice Fleury and Pierre Weigel for discussions and Dr. Kyoko Iwasaki-Yoshikane for CD measurements. This work was supported by grants from the Association pour la Recherche sur le Cancer [no. 3862], the Région de Pays de la Loire [MIAPS] and [CIMATH], the King Abdullah University of Science and Technology [KUK-11-008-23 to B.N.], and Swiss National Science Foundation [31003A-116275 to A.S.]. J.N. is a recipient of a Ph.D. fellowship from the Ligue Contre le Cancer Comité Loire Atlantique.
PublisherAmerican Chemical Society (ACS)
JournalJournal of Medicinal Chemistry
PubMed Central IDPMC2917172
CollectionsPublications Acknowledging KAUST Support
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